Fanconi anemia (FA) is an autosomal recessive disease which manifests increased risk of leukemia, regressive bone marrow failure, skeletal abnormalities, altered skin pigmentation and developmental delay. Therefore FA presents alterations in growth and development with anemia, and is an autosomal recessive disease with increased risk of cancer. There are eight complementation groups identified, indicating the involvement of multiple genes in the disease. This Program Project will use a molecular genetic approach to define the genetic elements causing Fanconi anemia and the function of the gene products in order to improve diagnosis and treatment. The concept of this project is to take a multi-disciplinary approach to the definition of the causes of Fanconi anemia at the molecular and cellular level. The clinical disciplines represented by the Investigators include medicine, pediatrics, medical genetics, hematology and oncology. The scientific areas of the investigations include molecular hematology, molecular genetics, mouse genetics, gene therapy, stem cell biology and DNA repair. The proposed project will have three investigative components and three core components: Project 1 will participate in cloning the FA-D group gene and analyze the function of the FA-D protein. Pathogenesis of FA as a result of crosslink repair defects will be tested in mouse models. Project 2 will participate in cloning FA-D and will build mouse models deficient in FA-D and FA-A gene products. Project3 will asess the apoptotic cytokine response defects in FA and define the molecular hematological defects in the mouse models. The Cytogenetics Core will test chromosome breakage in new Fanconi anemia cell line candidates and help map candidate Fanconi anemia genes. The Fanconi Anemia Cell Repository will identify Fanconi anemia cell lines for complementation testing and establish permanent cell lines for investigators as well as provide diagnostic procedures for FA patients and their providers.